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www.biopharminternational.com October 2020 BioPharm International eBook 37 Regulatory Sourcebook Process Development Clearly, the experimental activi- ties should be primarily conducted to address the identif ied areas of focus. Ta b l e I V sug ge st s a se r ie s of studies to investigate and acquire e x p e r i me nt a l k nowle dge on a freeze-dried product in the differ- ent unit operations of the manu- facturing process. Finally, Table V summarizes the most important formulation devel- opment studies for a solution and freeze-dried product. The final output of the design and exper imental phase is the update of the risk assessment as a consequence of the results of devel- opment studies: If there are some gaps, the mitigation actions should be defined, implemented, and ver- ified to define the manufacturing batch record to be used during process qualification. Moreover, an initial definition of the con- trol strategy might be developed; although, this initial hypothesis will be confirmed during stage 2. PROCESS PERFORMANCE QUALIFICATION (PPQ) The new concept of the process qualification (stage 2) starts with process design and continues for the entire lifecycle of the product (stage 3). PPQ shows that the pro- cess, operating within established pa ra meter s, ca n be per for med effectively and reproducibly to pro- duce a medicinal product meet- ing its QTPP. Another aim is to provide evidence that (at least) the identified risks, as described Compounding and filling Response (test)* Order of addition of components Appearance Stirrer type and speed Par ticulate matter Temperature Assay Time Degradation produc ts Irregular filling Content uniformity pH Freezing Response (test) Vial loading shelf temperature Appearance Ramp rate to final shelf temperature Porosity Final shelf temperature Solid state Hold time at final temperature Reconstitution time Annealing ( Y/N) Assay (proteins) Degradation produc ts (proteins) pH Par ticulate matter Primary drying Response (test) Ramp rate to final shelf temperature Appearance Shelf temperature Solid state Chamber pressure Reconstitution time Hold at final shelf temperature Assay Degradation produc ts Par ticulate matter Process analytical technology (PAT) option: primary drying end-point monitored by using a process analyzer. Secondary drying Response (test) Ramp rate to final shelf temperature Appearance Final shelf temperature Assay Hold at final shelf temperature Degradation produc ts Chamber pressure Residual moisture Residual solvent (if relevant) PAT option: residual moisture monitored by using a process analyzer. * The term response (test) refers to the potential impact of the process stage on drug product characteristics. Table IV. Potentially critical process parameters and response for a freeze-dried product.